The worldwide exploitation of antibiotics to treat infectious diseases has grown dramatically over the last forty years. In 1954, two million pounds of antibiotics were produced in the United States. Today, the figure exceeds 50 million pounds. According to the Centers Disease Control (CDC), humans consume 235 million doses of antibiotics annually.
Widespread misuse or overuse of antibiotics has fostered the spread of antibiotic resistance and has contributed to the development of a serious public health problem. Antibiotic resistance occurs when bacteria that cause infection are not killed by the antibiotics taken to stop the infection. The bacteria survive and continue to multiply, causing more harm. For example, the bacterium Staphylococous aureus is a major cause of hospital acquired infections that, historically, responded satisfactorily to the antibiotic vancomycin. Recently, however, many strains of S. aureus have been found to be resistant to vancomycin. Moreover, the death rates for some communicable diseases such as tuberculosis have started to rise again, in part because of increases in bacterial resistance to antibiotics.
Antibiotics are used therapeutically to treat bacterial infections. Several types of antibiotics, classified according to their mechanism of action, are currently employed. The known types of antibiotics include, e.g. cell wall synthesis inhibitors, cell membrane inhibitors, protein synthesis inhibitors and inhibitors that bind to or affect the synthesis of DNA or RNA.
Cell wall synthesis inhibitors, such as beta lactam antibiotics, generally inhibit some step in the synthesis of bacterial peptidoglycan. Penicillin is generally effective against non-resistant streptococcus, gonococcus and staphylococcus. Amoxycillin and Ampicillin have broadened spectra against Gram-negative bacteria. Cephalosporins are generally used as penicillin substitutes, against Gram-negative bacteria and in surgical prophylaxis. Monobactams are generally useful for the treatment of allergic individuals.
Numerous antibiotic agents, suitable for use in the treatment of bacteria-related diseases and disorders, are known and disclosed, e.g. in The Physician's Desk Reference (PDR), Medical Economics Company (Montvale, N.J.), (53rd Ed.), 1999; Mayo Medical Center Formulary, Unabridged Version, Mayo Clinic (Rochester, Minn.), January 1998; Merck Index: An Encyclopedia of Chemicals, Drugs and Biologicals, (11th Ed.), Merck & Co., Inc. (Rahway, N.J.), 1989; University of Wisconsin Antimicrobial Use Guide, http://www.medsch.wisc.edu/clinsci/5amcg/amcg.html; Introduction on the Use of the Antibiotics Guideline, of Specific Antibiotic Classes, Thomas Jefferson University, http://jeffiine.tju.edu/CWIS/OAC/antibiotics_guide/intro.html; and references cited therein.
The first carbapenem to be isolated was thienamycin, shown below, which was isolated from Streptomyces cattleya (U.S. Pat. No. 3,950,357) and was shown to have strong antibacterial activity, including potency against Pseudomonas spp. and β-lactamase stability (Kahan, J. S., et al., J. Antibiot., 32, pp. 1-12 (1979); Bodey, G. P., et al., Antimicrob. Agents Chemother., 15, pp. 518-521 (1979). The racemic synthesis of thienamycin was reported shortly thereafter by Merck (Johnston, D. B. R., et al., J. Am. Chem. Soc., 100, pp. 313-315 (1978); Bouffard, F. A., et al., J. Org. Chem., 45, 1130-1142 (1980)), as well as an asymmetric total synthesis (Salzmann, T. N., et al., J. Am. Chem. Soc. 102, pp. 6161-6163 (1980)). The nucleus and amino-containing side chain of this molecule,
however, contributed to its chemical instability. In addition to its potential to be hydrolyzed by the zinc-activated β-lactamase that is present in Bacillus species, Xanthomonas, Pseudomonas, and Bacteroides species (Saino, Y., et al., Antimicrob. Agents Chemother., 22, pp. 564-570 (1982); Yotsujii, A., et al., Antimicrob. Agents Chemother., 24, pp. 925-929 (1983)), chemical stability issues associated with the intermolecular aminolysis of the azetidinone (β-lactam) ring of one molecule of thienamycin by the primary amine in the cysteamine side chain of another thienamycin molecule, resulted in the use of thienamycin as a drug candidate to be abandoned.
As a result of the problems associated with thienamycin, N-formimidoyl thienamycin, known as imipenem, was synthesized (Leanza, W. J., et al., J. Med. Chem., 22, pp. 1435-1436 (1979)). This compound bears a more basic amidine functionality on the 2′ side chain, which is protonated at physiological pH, preventing the compound from initiating a nucleophilic attack on another imipenem molecule.

However, poor urinary tract recovery from test subjects revealed an instability of this compound to the mammalian β-lactamase renal dehydropeptidase-I (DHP-I) (Shimada, J., et al., Drugs Exp Clin Res., 20, pp. 241-245 (1994)). Consequently, the compound cilastatin was developed for use in co-administration in order to prevent hydrolysis and degredation by DHP-I; this combination therapy is currently prescribed under the name Primaxin® (Merck Frosst Std).
In response to the problem of carbapenems to destruction by renal dehydropeptidase-1, the carbapenem antibiotic meropenem (SM7338) (shown below), was developed (see, Edwards, J. R., et al., Antimicrob. Agents Chemother., 33, pp. 215-222 (1989); Neu, H. C., et al., Antimicrob. Agents Chemother., 33, pp. 1009-1018 (1989)).
This compound was shown to be active against a large number of Gram-negative bacteria. The drug is currently prescribed for intravenous use (Merrem® IV; AstraZeneca) in the treatment of intra-abdominal infections and bacterial meningitis.
The carbapenem ertapenem (formerly MK-0826; Cunha, B. A., Drugs of Today, 38, pp. 195-213 (2002)) was the first of a group of carbapenems with potential against methicillin-resistant staphylococci (MRS) shown to be useful as a long-acting, parenteral carbapenem (Shah, P. M., et al., J. Antimicrob. Chemother., 52, pp. 538-542 (2003); Aldridge, K. E., Diagn. Microbiol. Infect. Dis., 44(2), pp. 181-6 (2002)). It is suitable for administration both as a single-agent (e.g., co-administration with a compound such as cilastatin is not required), or by the intravenous or intramuscular route (Legua, P., et al., Clin. Therapeut., 24, pp. 434-444 (2002); Majumdar, A. K., et al., Antimicrob. Agents Chemother., 46, pp. 3506-3511 (2002)). Ertapenem has received regulatory approval in both the United States (November, 2001) and the European Union (April, 2002).
One carbapenem having a fused pyrazole ring system (L-627; Biapenem) was developed by Lederle Ltd. (Japan), and introduced a methyl radical at the 1-β position of the carbapenem skeleton (see, U.S. Pat. No. 4,866,171). This structural modification reportedly gave biapenem stability against hydrolysis by kidney dehydropeptidase, making co-administration of a dehydropeptidase inhibitor unnecessary.
More recently, a new, injectable 1-β-methyl carbapenem antibiotic having an (R)-1-hydroxymethyl-methylaminopropyl group exhibiting both broad spectrum, potent antibacterial activity (BO-2727) and having antipseudomonal activity has been reported (Nakagawa, S., et al., Antimicrob. Agents Chemother., 37, pp. 2756-2759 (1993); Hazumi, N., et al., Antimicrob. Agents Chemother., 39, pp. 702-706 (1995).

Since the discovery of thienamycin having a potential antimicrobial activity against Gram-negative and Gram-positive bacteria, studies on the syntheses of carbapenem derivatives which are analogous to thienamycin have been widely developed. As a result, it was found that carbapenem derivatives having, as their 2-side chain, a substituent derived from 4-hydroxy-proline exhibit a potential antimicrobial activity and are useful as medicines or as intermediates for compounds possessing antimicrobial activity.
1-β-methyl carbapenem antibiotics, are particularly well known for treating a broad spectrum of gram-negative and gram-positive bacterial infections. See for example U.S. Pat. No. 4,962,103; U.S. Pat. No. 4,933,333; U.S. Pat. No. 4,943,569; U.S. Pat. No. 5,122,604; U.S. Pat. No. 5,034,384 and U.S. Pat. No. 5,011,832.
U.S. Pat. No. 6,255,300 to Merck & Co. describes certain carbapenem antibacterial agents in which the carbapenem nucleus is substituted with an iodo-phenyl linked through a methyl-oxygen linkage. The patent states that these compounds are useful against gram positive bacterial infections. Similarly, U.S. Pat. No. 6,310,055 provides carbapenem compounds with aromatic side chains that are halogen substituted, linked thorough an alkoxy unsaturated group.
European Publication No. 0 292 191 to Merck & Co. describes certain 2-(substituted methyl)-1-alkylcarbapenem compounds useful as antibiotic agents.
U.S. Pat. No. 6,399,597, also to Merck & Co. describes certain napthosultam compounds that are allegedly useful in the treatment of certain drug resistant bacterial infections.
U.S. Pat. No. 7,683,049 to FOB Synthesis, Inc. describes certain β-methyl carbapenem compounds for the treatment of gram-negative bacterial infections.
Because of the drug-resistance challenges associated with treating bacterial infections, there remains a need for new antimicrobial agents.
Therefore, it is one object of the present invention to provide novel β-methylcompounds carbapenems that are effective antimicrobial agents.
It is another object of the present invention to provide methods for the treatment of gram-negative bacteria, which optionally can be drug-resistant and/or multi-drug resistant.